The genes for lens major intrinsic proteins (MIPs) encode the most abundant plasma membrane proteins in lens fiber cells and both genes have been linked with hereditary forms of cataract in humans. We have identified several strains of mice that also inherit mutations in MIP genes and these animals provide relevant model systems for studying MIP-related cataract in humans. [unreadable] [unreadable] In specific aim 1 we will use PCR-based sequencing, Northern blot hybridization, and immuno-chemical techniques to compare and contrast the degree of MIP gone disruption in two strains of MIP-deficient mice. In specific aim 2 we will use confocal and electron microscopy techniques to compare and contrast the effects of MIP gene deficiencies on lens fiber cell structure and organization. In addition, we will use tracer flux and laser focusing techniques to determine the effects of MIP-deficiencies on lens optical quality. In specific aim 3 we will compare and contrast the role of caspase and calpain proteases in lens fiber cell death associated with cataractogenesis in MIP-mutant versus MIP-deficient mice. [unreadable] [unreadable] Results from these studies will provide new insights regarding (1) the pathogenetic mechanisms underlying MIP-related cataract in humans and (2) the physiological functions of MIPs in establishing the unique fiber cell architecture of the crystalline lens.